We propose a Phase I STTR study to develop a novel human immunodeficiency virus (HIV) vaccine strategy with the potential of world-wide efficacy. The HIV/AIDS pandemic remains a major global burden. No test vaccine based on traditional scientific principles has induced sufficiently protective immunity to HIV. Induction of neutralizing antibodies (Abs), the cornerstone of vaccination against microbes, has been thwarted by: (a) mutability of the immunodominant viral epitopes, and (b) poor adaptive immunological response to conserved epitopes important in virus-host cell interactions. CD4 binding by the HIV envelope glycoprotein gp120 is an obligatory step in the HIV life cycle. gp120 residues 421-433 constitute the mostly-conserved core of the CD4 binding site (CD4BScore). Except for rare survivors of prolonged HIV infection, the immune system does not support the production of anti-CD4BScore Abs. The proposed Phase I project focuses on electrophilic immunogens (E-immunogens) derived from the novel chemical engineering strategy termed Covalent Vaccination concept. E-immunogens hold the potential of inducing the synthesis of protective Abs that is beyond the scope of the physiological immune response. We will carry out the following developmental studies: (i) Characterize and compare the protective anti-HIV properties of rabbit and mouse antibodies raised by immunization with electrophilic derivatives of purified gp120 and synthetic 416-433 peptide; (ii) Maximize the antibody response to the lead E-immunogen using alternate adjuvants. Proving preclinical proof-of-principle for covalent vaccination as an effective approach in the present project is an important step in translating this approach for HIV vaccination.